Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001045640 | SCV001209504 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-11-29 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Asn2624 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 11700157, 19293843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 549437). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 10756346, 19293843, 31211624; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2624 of the FBN1 protein (p.Asn2624Ser). |
| Institute of Medical Genetics and Applied Genomics, |
RCV000663989 | SCV004231848 | pathogenic | Marfan syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | assumed de novo, but without confirmation of paternity and maternity (1 heterozygous case) |
| Laboratory for Molecular Medicine, |
RCV000663989 | SCV004847651 | likely pathogenic | Marfan syndrome | 2019-03-07 | criteria provided, single submitter | clinical testing | The p.Asn2624Ser variant in FBN1 has been reported as a de novo variant in one individual with Marfan syndrome (Stheneur 2009) and was also identified in one individual with TAAD (Wolford 2018 preprint). In addition, this variant is located in the calcium-binding consensus sequence and two other amino acid substitions (p.Asn2624Thr and p.Asn2624Lys) have been identified in individuals with clinical features of Marfan syndrome. This variant was absent from large population studies and is reported in ClinVar (Variation ID: 539510). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM2; PM6; PS4_Supporting. |
| Center for Medical Genetics Ghent, |
RCV000663989 | SCV000787373 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |